Derivatives of 6,7-benzomorphan

ABSTRACT

A benzomorphan selected from the compounds of the formula   WHEREIN R is hydrogen or acyl and R is a saturated or saturated acyclic hydrocarbon radical with three carbon atoms and their non-toxic, pharmacologically acceptable acid addition and quaternary salts exhibit strong analgesic activities without the undesirable side effects of morphine.

United States Patent [191 Freter et al.

[ 1 Mar. 27, 1973 [541 DERIVATIVES OF 6,7-

BENZOMORPHAN [75] Inventors: Kurt Freter; Karl Zeile, both of Ingelheimam Rhine, Germany [73] Assignee: C. H. Boehringer Sohn, lngelheim amRhine, Germany 22 Filed: on. 12, 1960 21 Appl. No.: 62,099

[30] Foreign Application Priority Data OTHER PUBLlCATlONS May et al., J.Org. Chem. 22, 1366-1369 (1957). May et al., J. Org. Chem. 24, 1432-1437(1959). May et al., J. Org. Chem. 25, 984-986 (1960).

Grussner et al., Helv. Chim. Acta 39, 436-440 (1956).

Ager et al., J. Org. Chem. 25, 984-986 (1960). Archer et al., J. Med.Chem. 7, 123-127 (1964).

Primary Examiner-Henry R. Jiles Assistant ExaminerG. Thomas ToddAttorney-Hammond & Littell [57] ABSTRACT A benzomorphan selected fromthe compounds of the wherein R is hydrogen or acyl and R is a saturatedor saturated acyclic hydrocarbon radical with three carbon atoms andtheir non-toxic, pharmacologically acceptable acid addition andquaternary salts exhibit strong analgesic activities without theundesirable side effects of morphine.

7 Claims, N0 Drawings 1 DERIVATIVES OF 6,7-BENZOMORPHAN This inventionrelates to novel derivatives of 6,7- benzomorphan, and more particularlyto compounds having the structural formula wherein R is hydrogen oracyl, especially lower alkanoyl, and R is a saturated or unsaturatedacyclic hydrocarbon radical with 3 carbon atoms, and their non-toxic,pharmacologically acceptable acid addition and quaternary salts.

in an article by B. May and N. Eddy, J. Organ.

Chem., 24, 294 (1959) it is reported that the 6,7-

benzomorphan derivative 2-hydroxy-5,9-dimethyl-2-(N-B-phenethyl)-6,7-benzomorphan (also known as phenazocine) of theformula C Hz C Ha exhibits analgesic properties the intensity of whichexceeds those of morphine manifold. However, pharmacological andclinical tests of this compound have shown that this high analgesicactivity is also accompanied by the undesirable side effect whichmorphine produces, namely drowsiness, respiratory depression, miosis,hypothermia and the like. Moreover, the compound described by May andEddy produces addiction after extended regular use.

It has long been the endeavor of pharmacologists and chemists to providenew analgesics which exhibit an analgesic activity about equal to orhigher than that of morphine without the undesirable side effects of theopium alkaloids, particularly with respect to addiction.

In pursuit of this endeavor we have made the surprising discovery thatcompounds having the structural formula I above and their non-toxic,pharmacologically acceptable acid addition and quaternary salts exhibitstrong analgesic activities without the undesirable side effects ofmorphine. Moreover, the compounds according to the present invention areeffective morphine antagonists, which assures the availability ofanalgesics free from habit-forming properties.

The novel derivatives of 6,7-benzomorphan embraced by formula 1 abovemay be prepared by reacting 2'-hydroxy-5,9-dimethyl-6,7-benzomorphanwith an equimolar amount of an alkylating agent, such as a compound ofthe formula R Hal (n) wherein R, has the meaning previously defined andHal is a halogen, especially chlorine, bromine or iodine, undercustomary alkylating conditions to produce a compound of the formulaCHaO-N*R1 I CH;

CH2CH2 (III) wherein R has the meanings previously defined. The abovereaction is advantageously carried out in an inert organic solventwherein the reactants are soluble, such as alcohols or tetrahydrofuran,preferably under exclusion of water and at elevated temperatures, suchas at the boiling point of the reaction mixture. The process producesespecially good yields when an acid-neutralizing agent capable of tyingup the hydrogen halide formed by the reaction is added to the reactionmixture in an amount in excess of the molar amount needed toneutralize'the calculated quantity of hydrogen halide. Alkali metalbi-carbonates are particularly suited for this purpose.

If it is desired to obtain compounds of the formula I wherein R is acyl,especially lower alkanoyl, the 2'- hydroxy compound of the formula IIIis reacted with an acylating agent, such as a lower alkanoic acidanhydride, to produce a compound of the formula (Div-'JNIM CH2 CH2wherein R is acyl, especially lower alkanoyl, and R has the meaningspreviously defined.

If it is desired to prepare non-toxic, pharmacologically acceptable acidaddition salts of the free bases, compounds III or IV are reacted withan inorganicor organic acid comprising a non-toxic anion. Typicalexamples of such acids are hydrochloric acid, hydrogen bromide, hydrogeniodide, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citricacid, tartaric acid, gluconic acid, ascorbic acid, methanesulfonic acid,benzoic acid and toluenesulfonic acid.

If it is desired to prepare non-toxic, pharmacologically acceptablequaternary salts of the free bases, compounds III or IV are reacted witha quaternizing agent of the formula R Hal wherein R is a saturated orunsaturated acyclic hydrocarbon radical with 3 carbon atoms and Hal ischlorine, bromine or iodine, in the presence of an inert organicsolvent, especially a lcetone, at elevated temperatures, preferably atthe boiling point of the reaction mixture. In place of the inert organicsolvent it is also possible to use a large excess of the quaternizingagent V. The quaternizing procedure thus results in benzomorphaniumcompounds of the formula wherein R is hydrogen or acyl, especially loweralkanoyl, R, and R are identical or different saturated or unsaturatedacyclic hydrocarbon radicals with 3 carbon atoms and Hal is a non-toxic,pharmacologically acceptable halogen anion, i.e. chlorine, bromine oriodine.

In the preparation of those quaternary benzomorphanium salts wherein Rand R are identical, the introduction of these radicals into thebenzomorphan molecule, that is the alkylation and quaternization steps,may be accomplished in a single step by reacting compound [11 with atleast two mol equivalents of compound 11. However, this method producesless favorable yields than the analogous twostep method. It is thereforepreferred to perform the alkylation and quaternization steps in twoseparate operations with intermediate isolation of the tertiary base 111or IV. Of course, if quaternary benzomorphanium compounds of the formulaVI are to be prepared wherein R and R are different from each other, thealkylation and quaternization steps must necessarily be performed in twoseparate operations. Moreover, if R and R are different, a reversal inthe sequence of their introduction into the benzomorphan molecule maylead to stereoisomeric forms of the same compound.

The 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan used as the startingmaterial in the preparation of the compounds of the present inventionwas obtained by the method described in the article of May and Eddy(loc. cit.), i.e., by subjecting 2'-acetoxy-2,5,9-trimethyl-6,7-benzomorphan to cyanogen bromide degradation.

The following examples will further illustrate the present invention andenable others skilled in the art to understand it more completely. It isunderstood, however, that these examples are given for purposes ofillustration only and are not intended as a delineation of the scope ofthe invention.

EXAMPLE 1 Preparation of 2-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan extract solutions were again evaporated in vacuo todryness. The residue was taken up in 20 cc hydrochloric acid and theresulting solution was shaken for half an hour with about 0.3 gm ofdecolorizing charcoal. Thereafter, the solution was filtered, thefiltrate was cooled on an ice bath and then made alkaline withconcentrated ammonia while stirring. A precipitate formed which wasseparated by vacuum filtration, washed with water and dried. 1.5 gm ofpractically pure 2'-hydroxy- 5,9-dimethyl-2-a1lyl-6,7-benzomorphanhaving a melting point of to 152C. were obtained. For analysis, theproduct thus obtained was recrystallized from acetone, whereupon it hada melting point of to 153C.

Analysis: C H NO; mol. wt. 257.2

Calculated: C 79.40% H 8.95%

Found: C 79.07% H 8.88%

Probable structural formula:

lts hydrochloric acid addition salt, obtained by dissolving the freebase in hydrochloric acid, evaporating the solution to dryness andrecrystallizing the residue from a mixture of ethanol and ether (1:1),had a melting point of 154C.

EXAMPLE 11 Preparation of 2-hydroxy-5 ,9-dimethyl-2-n-propyl-6,7-benzomorphan A mixture of 1.5 gm 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.18 gm n-propyl iodide, 0.70 gm sodium bicarbonate and 50cc ethanol was refluxed for 7 hours and the resulting reaction mixturewas worked up as described in Example I. 1.1 gm of 2'-hydroxy-5,9-dimethyl-2-n-propyl-6,7-benzomorphan were obtained. Recrystallized frommethanol, the product had a melting point of 174C. Probable structuralformula:

[ts hydrobromic acid addition salt, obtained with l-lBr in a manneranalogous to that described in the preceding Example for the preparationof the hydrochloride,

had a melting point of 130C. after recrystallization from acetone.

EXAMPLE Ill Preparation of 2-hydroxy-5 ,9-dimethyl-2,2-diallyl-6,7-benzomorphanium bromide 750 mgm 2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan were dissolved in 25 cc acetone. Thereafter, 25 cc allylbromide were added to the solution, and the resulting mixture wasrefluxed for 5 hours. A crystalline precipitate was formed. The reactionmixture was then cooled at +5C. for 12 hours, to bring the precipitationof the reaction product to completion. The precipitate was separated byvacuum filtration, washed with ice-cold acetone and recrystallized fromethanol. 820 mgm of 2'-hydroxy-5,9-dimethyl-2,2-diallyl-6,7-benzomorphanium bromide having a melting point of 228 to 230C. andthe probable structural formula were obtained.

Analysis: C H NOBr; molecular weight 378.1 Calculated: C 63.49% H 7.41%

Found: C 63.44% H 7.40%

EXAMPLE IV Preparation of 2 '-hydroxy-5,9-dimethyl-2,2-di-npropyl-6,7-benzomorphanium bromide (HIT-CH2 ClixEXAMPLE V Preparation of 2'-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium bromide 500 mgm of2'-hydroxy-2-n-propyl-5,9-dimethyl- 6,7-benzomorphan were dissolved incc acetone, and 10 cc propargyl bromide were added to the solution. Theresulting reaction mixture was refluxed for 2 hours and was then allowedto cool, whereby a crystalline precipitate separated out. Theprecipitate was filtered off and recrystallized from ethanol, yielding aproduct having a melting point of 218C. and the probable structuralformula l W /cur oH2oHa CH; N

CH:CECH Ha O i CH2 CH9 EXAMPLE VI Preparation of2'-hydroxy-5,9-dimethyl-2-n-propyl-2- allyl-6,7-benzomorphanium bromidePreparation of 2'-acetoxy-5,9-dimethyl-2-n-propyl-6,7- benzomorphan Amixture of 7 gm 2'-h'ydroxy-2-n-propyl-5,9- dimethyl-6,7-benzomorphanand 35 cc acetic acid anhydride was boiled for 20 minutes and was thenallowed to cool. Thereafter, it was combined with five times its volumeof ice and the resulting mixture was made alkaline with concentratedammonia. An oily substance separated out which was extracted with ether.The ether extract solution was dried over magnesium sulfate, the etherwas evaporated in vacuo and the residue was distilled. 5 gm of a light,viscous oil were obtained which had a boiling point of to C., at 0.2 mmHg and the probable structural formula CHa-CO O EXAMPLE vm Preparationof 2'-acetoxy-5,9-dimethyl-2-n-propyl-2- allyl-6,7-benzomorphaniumbromide 2 gm of 2'-acetoxy-5,9-dimethyl-2-n-propyl-6,7-

- benzomorphan were dissolved in 15 cc allyl bromide.

The resulting solution was refluxed for 3 hours. A recrystallineprecipitate formed which was separated by vacuum filtration andrecrystallized from ethanol. The product had a melting point of 202C.and the probable structural formula CHa-COO For therapeutic purposes thecompounds according to the present invention are administered in dosagesof 5 to 80 mgm, and preferably to 50 mgm, in the form of tablets,injectable solutions or suppositories. The following are typicalexamples of such compositions:

l Tablets: Each tablet contains:

2'-hydroxy-5,9-dimethyl-2,2-diallyl- 6,7-benzomorphaniurn bromide 0.03gm Lactose 0.11 gm Starch 0.065gm Stearic acid 0.00lgm Talcum 0.009grnFinely milled SiO, 0.005gm Weight of each tablet 0.220gm 2. Injectablesolution in 1 cc ampules:

Each ampule contains:

2'-hydroxy-5,9-dimethyl-2,2-diallyl- 6,7benzomorphanium bromide 0.02 gmSodium chloride 0.0070gm Hydrochloric acid (0.001 N) q.s.ad l.0 ml 3.Suppositories:

Each suppository contains:

2'-hydroxy-5,9-dimethyl-2-npropyl-6,7-benzomorphan 0.0l gm Lactose 0.04gm Suppository mass l.

Weight of each suppository It should be understood that the abovecompositions are merely illustrative examples of the various forms inwhich the active compounds according to the present invention may betherapeutically administered. It is self-evident that any other compoundembraced by formula I above or the corresponding non-toxic, phar- 0macologically acceptable acid addition and quaternary salts may besubstituted for the particular active ingredient given in the aboveprescription examples. Similarly, the dosages of active ingredient inthese compositions may be varied within the above indicated limits tosuit the particular requirements.

While I have set forth a number of specific examples to m invention, itis to be understood that these speci c embodiments are given forpurposes of illustra- 2-hydroxy-5,9dimethyl-2-allyl-6,7-

in which R is a member of the group consisting of CH CH=Cl-l and CH-Cl-l#Il-l.

TTED STATES PATENT OFFICE I CERTIFICATE OF CORRECTION Patent No. Q DatedMarch 27, 1973 Inventor) KURT FRETER and KARL ZEILE It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shdwn below:

I 173] Assignee: "c. H. BOEHRINGER SOHN" sh'uld read j A --By MesneAssignments to BOEHRINGER INGELHEIM G.m.b.H-

Column 6, that part of the 2nd formula which reads H I -V N .7

CH -CHC=H should read cH :H=0H

I Column 8, last line, correct "-CH -CH CH" to read CH '-CECH-- "si nemand sealed this 16th say of A r-i1 197A,

( AL) i A Attssb: A 4

' c MARSHALL DANN 4 h 1 I 0 "a '1 EL o EDWARD h FLJJTLJH' t2,Commissioner of Patents- Attes ting Gfficsr

2. 2''-hydroxy-5,9-dimethyl-2-n-propyl-6,7-benzomorphan. 3.2''-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan. 4.2''-hydroxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide.5.2''-hydroxy-5,9-dimethyl-2-n-propyl-2-propargyl-6,7-benzomorphanium-bromide.6.2''-acetoxy-5,9-dimethyl-2-n-propyl-2-allyl-6,7-benzomorphanium-bromide.7. The compound of the formula